A central feature of HIV-1 pathogenesis is vigorous and chronic virus replication in the face of T cell immunity, especially CD8+ T cells. HIV-1 (and SIV) can exploit dendritic cells (DCs), for purposes of transmission and replication. For example DCs can serve as conduits to transport virus to T cells and as activators to allow HIV-1 replication in T cells. Functional subsets of DCs have now been distinguished. We will study HIV-1 pathogenesis in the context of 3 major DC subsets: monocyte-derived DCs, Langerhans cells, and new plasmacytoid cells. We will develop methods for preparing these subsets in larger numbers and for controlling their maturation in culture, emphasizing G-CSF mobilized blood as the starting population. In vivo, we will use an expanding panel of monoclonal antibodies to identify and localize macrophages and DC subsets. We will assess cytokine production and the new DC-SIGN receptor for HIV-1. In lymphoid tissues. we will place new emphasis on thymus and mucosa associated lymphoid tissue, the latter recently identified as a major site for HIV-1 (and SIV) replication. As part of a European consortium, we will also study non-lymphoid tissues, like brain and gut, from SIV-infected monkeys. We will follow the virologic consequences of HIV-1 infection of each DC subset. In addition to viral life cycle, we will assess DC maturation and cytokine production. Utilizing pseudotyped viruses and select DC subsets to achieve high level expression of' HIV-1, we will examine the primary and secondary T cell responses to HIV-1. We will determine if the quality of the HIV-1 specific immune response is altered at the level of DCs. A skewing towards Th2 or T regulatory cell development, or a silencing of CD8+ T cells, could provide strategies for HIV-1 to avoid potentially protective immune responses.